Volatile Anesthetics and Respiratory Neurotransmission

描述(由申请人提供)：亚麻醉剂浓度的挥发性麻醉剂有效地抑制上呼吸道防御机制。特别是，在吸气期间维持呼吸道通畅的舌下运动控制严重受损。该方案的总体目标是描述挥发性麻醉剂对活体中自发活动的哺乳动物吸气下运动神经元(IHMN)中特定突触机制和神经元兴奋性的作用。虽然体外研究已经确定了麻醉剂诱导的抑郁的潜在机制，但这一建议是独特的，因为我们专注于体内条件下完整神经网络中功能识别的IHMN，其中神经递质在生理相关的水平上释放。我们的总体假设是：1)IHMN的活动依赖于由配体门控的谷氨酸、GABA、甘氨酸和G蛋白偶联的5-羟色胺和肾上腺素能受体介导的突触输入；2)挥发性麻醉剂对神经元活动的影响是由于抑制兴奋性和增强抑制性突触神经传递，而不是非突触介导的内在膜机制，如K+电导的变化。记录IHMN的动作电位，结合局部压力微喷射神经递质激动剂和拮抗剂，将被用来检验麻醉诱导的兴奋性和抑制性神经传递以及内在神经元兴奋性改变的相对重要性。已经开发了三个特定的目标来在去大脑的犬类模型中验证我们的假设。在具体目标1中，我们将确定IHMN中的关键神经递质，并测定它们的生理受体活性。在具体目标2中，我们将确定麻醉下浓度的挥发性麻醉药对IHMN中关键神经递质系统的整体突触传递的影响。在具体目标3中，我们将确定挥发性麻醉剂对IHMN中关键神经递质突触后受体反应的影响。我们的研究将有助于我们理解挥发性麻醉药在围手术期对上呼吸道功能的影响，并可能提出合理的基于机制的治疗干预措施，以减轻术后患者呼吸道相关并发症的高风险。

DESCRIPTION (provided by applicant): Subanesthetic concentrations of volatile anesthetics potently depress upper airway defense mechanisms. In particular, hypoglossal motor control of the tongue that maintains airway patency during inspiration is severely compromised. The overall goal of this proposal is to characterize the actions of volatile anesthetics on specific synaptic mechanisms and neuronal excitability within spontaneously active mammalian inspiratory hypoglossal motoneurons (IHMNs) in vivo. While in vitro studies have identified potential mechanisms for anesthetic-induced depression, this proposal is unique because we focus on functionally identified IHMNs in an intact neuronal network under in vivo conditions, where neurotransmitters are released at physiologically relevant levels. Our overall hypothesis is 1) that the activity of IHMNs is dependent on synaptic inputs mediated by ligand-gated glutamatergic, GABAergic, and glycinergic and G-protein coupled serotonergic and adrenergic receptors, and 2) the effects of volatile anesthetics on neuronal activity are due to depression of excitatory and enhancement of inhibitory synaptic neurotransmission, rather than non-synaptically mediated intrinsic membrane mechanisms such as changes in K+conductance. Recordings of action potentials from IHMNs in conjunction with localized pressure microejection of neurotransmitter agonists and antagonists will be used to examine the relative importance of anesthetic-induced alterations on excitatory and inhibitory neurotransmission and intrinsic neuronal excitability. Three specific aims have been developed to test our hypothesis in a decerebrate canine model. In specific aim 1, we will identify the key contributing neurotransmitters in IHMNs and determine their physiological receptor activity. In specific aim 2, we will determine the effect of subanesthetic concentrations of volatile anesthetics on overall synaptic transmission of the key neurotransmitter systems in IHMNs. In specific aim 3, we will determine the effects of volatile anesthetics on the postsynaptic receptor responses for the key contributing neurotransmitters in IHMNs. The insights that will be gained from our proposed studies will contribute to our understanding of the effects of volatile anesthetics on upper airway function in the perioperative period and may suggest rational mechanism-based therapeutic interventions to mitigate these effects in the postoperative setting when patients are at high risk of airway- related morbidity.